Acute-on-chronic liver failure vs. traditional acute decompensation of cirrhosis
2018; Elsevier BV; Volume: 69; Issue: 6 Linguagem: Inglês
10.1016/j.jhep.2018.08.024
ISSN1600-0641
AutoresThierry Gustot, Richard Moreau,
Tópico(s)Drug-Induced Hepatotoxicity and Protection
ResumoInfluenza virus infection as precipitating event of acute-on-chronic liver failureJournal of HepatologyVol. 70Issue 4PreviewWith great interest we have read the outstanding Grand Rounds article by Gustot et al. describing the current management of acute-on-chronic liver failure (ACLF),1 which is a frequent and devastating complication of liver cirrhosis with mortality rates of up to 80% within 28 days. Specific hepatic and extrahepatic organ failures are the defining feature of ACLF and discriminate ACLF from classical decompensation of liver cirrhosis.1 Full-Text PDF A 34-year-old woman with a history of chronic HCV-related cirrhosis was admitted to the hospital emergency department for an acute decompensation characterised by jaundice and ascites. A diagnosis of community-acquired spontaneous bacterial peritonitis complicated by bacteraemia with Escherichia coli was made. Despite prompt, adequate antibiotic treatment (ceftriaxone for 7 days), albumin infusion and adequate response (decrease of at least 25% of ascitic neutrophils at 48 h after the start of antibiotic), physicians observed a severe clinical deterioration with the development of neurological and respiratory failure. The patient was referred to the intensive care unit of University Hospital. At admission, the patient was mechanically ventilated with severe respiratory parameters (low tidal volume, positive end expiratory pressure [PEEP] of 15 cm H2O and fractional inspired oxygen [FiO2] 50%, resulting in arterial oxygen partial pressure [PaO2] of 61 mmHg, PaO2/FiO2 ratio of 122), stage IV hepatic encephalopathy, type I hepatorenal syndrome that responded to terlipressin 4 mg per day (creatinine 1.1 mg/dl), international normalized ratio (INR) 3.58, and total bilirubin 22 mg/dl. Thoracic computed tomography showed slight bilateral pleural effusion and left basal condensation. A systematic microbiological screening including bronchoalveolar lavage, blood, urinary and ascitic cultures did not demonstrate any overt infection. After three days of intensive management, the clinical situation did not improve significantly (mechanical ventilation with PEEP 12 cmH2O, FiO2 50%, PaO2 65 mmHg and a PaO2/FiO2 ratio of 130, stage IV hepatic encephalopathy, serum ammonia level of 376 µg/dl, INR 2.98, total bilirubin 30 mg/dl, creatinine 0.9 mg/dl under terlipressin 4 mg per day). Thus, orthotopic liver transplantation was considered the only long-term life-saving option for this patient. However, this candidate seemed to be too sick to receive an organ. This case prompts many clinical questions, including: I.Are there specificities in this acute decompensation of cirrhosis? Is the concept of ACLF relevant for this case?II.Which precipitating events and pathogenic mechanisms are responsible for ACLF?III.Do we have tools to predict outcomes and clinical courses for ACLF?IV.What are the current management strategies, supported by evidence, for patients with ACLF?V.Is salvage liver transplantation a reasonable therapeutic option for ACLF? What is the ideal timing for liver transplantation?VI.Are there therapeutic (including experimental) strategies to improve survival or to bridge the patient to liver transplantation? Patients with decompensated cirrhosis exhibit clinical heterogeneity, which is associated with different prognoses. These patients must be stratified to define appropriate management. Some authors have suggested stratifying decompensation into three stages based on increasing two-year risk of death: patients who experience variceal bleeding alone (without other decompensating events) (20%), those with any first non-bleeding decompensating event (24%), or any second decompensating event (50–78%).[1]D'Amico G. Morabito A. D'Amico M. Pasta L. Malizia G. Rebora P. et al.New concepts on the clinical course and stratification of compensated and decompensated cirrhosis.Hepatol Int. 2017; https://doi.org/10.1007/s12072-017-9808-zCrossref PubMed Scopus (54) Google Scholar Moreover, beyond these stages, a more advanced stage has been suggested for patients with very bad short-term outcomes, including those with bacterial infections.[2]Arvaniti V. D'Amico G. Fede G. Manousou P. Tsochatzis E. Pleguezuelo M. et al.Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.Gastroenterology. 2010; 139 (1256.e1–e5): 1246-1256https://doi.org/10.1053/j.gastro.2010.06.019Abstract Full Text Full Text PDF PubMed Scopus (761) Google Scholar The term "acute-on-chronic liver failure (ACLF)" was first introduced to characterise this poorly defined situation.[3]Jalan R. Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options.Blood Purif. 2002; 20: 252-261https://doi.org/10.1159/000047017Crossref PubMed Scopus (242) Google Scholar The first definition was established by a consensus of the Asian Pacific Association for the Study of the Liver (APASL) who defined ACLF as "an acute hepatic insult manifesting as jaundice (total bilirubin ≥5 mg/dl) and coagulopathy (INR ≥1.5), complicated within four weeks by ascites and/or encephalopathy in a patient with chronic liver disease".[4]Sarin S.K. Kumar A. Almeida J.A. Chawla Y.K. Fan S.T. Garg H. et al.Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL).Hepatol Int. 2009; 3: 269-282https://doi.org/10.1007/s12072-008-9106-xCrossref PubMed Scopus (653) Google Scholar Thirty-day mortality is estimated to be between 25% and 37% when APASL criteria are fulfilled, but the presence and severity of organ failures (OFs) defined by the sequential organ failure assessment (SOFA) score discriminates patients with different prognoses (58% with OF and 8% without).5Jalan R. Stadlbauer V. Sen S. Cheshire L. Chang Y.-M. Mookerjee R.P. Role of predisposition, injury, response and organ failure in the prognosis of patients with acute-on-chronic liver failure: a prospective cohort study.Crit Care Lond Engl. 2012; 16: R227https://doi.org/10.1186/cc11882Crossref PubMed Scopus (88) Google Scholar, 6Dhiman R.K. Agrawal S. Gupta T. Duseja A. Chawla Y. Chronic Liver Failure-Sequential Organ Failure Assessment is better than the Asia-Pacific Association for the Study of Liver criteria for defining acute-on-chronic liver failure and predicting outcome.World J Gastroenterol. 2014; 20: 14934-14941https://doi.org/10.3748/wjg.v20.i40.14934Crossref PubMed Scopus (66) Google Scholar A large, multicentre prospective, observational study (CANONIC study) in 1,343 patients with cirrhosis who were hospitalised for an acute decompensation (AD) of cirrhosis (large ascites, hepatic encephalopathy [HE], gastrointestinal haemorrhage and/or bacterial infection), provided the first evidence-based diagnostic criteria that permitted physicians to distinguish between ACLF and 'mere' AD (i.e., traditional AD) (Table 1).[7]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437.e1–e9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042Abstract Full Text Full Text PDF PubMed Scopus (1769) Google Scholar In this last study, 28-day and 90-day mortality rates were higher among patients who had ACLF at enrolment than among those who had traditional AD (34% and 51% vs. 5% and 14%, respectively). Large observational studies have been performed using prespecified ACLF criteria in patients with cirrhosis who were admitted to hospital, in the context of the North American Consortium for the Study of End-Stage Liver Disease (NACSELD).8Bajaj J.S. O'Leary J.G. Reddy K.R. Wong F. Biggins S.W. Patton H. et al.Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures.Hepatol Baltim Md. 2014; 60: 250-256https://doi.org/10.1002/hep.27077Crossref PubMed Scopus (340) Google Scholar, 9O'Leary J.G. Reddy K.R. Garcia-Tsao G. Biggins S.W. Wong F. Fallon M.B. et al.NACSELD Acute-on-Chronic Liver Failure (NACSELD-ACLF) Score Predicts 30-Day Survival in Hospitalized Patients with Cirrhosis.Hepatol Baltim Md. 2018; https://doi.org/10.1002/hep.29773Crossref Scopus (141) Google Scholar Of note, NACSELD defined ACLF by the presence of at least two very severe extrahepatic OFs (shock, grade III/IV HE, renal replacement therapy, or mechanical ventilation), which are much more stringent criteria than those of the European Association for the Study of the Liver – Chronic Liver Failure (EASL-CLIF) consortium or the APASL. The NACSELD-defined ACLF is associated with a 30-day mortality rate of 41% compared to 7% for patients without ACLF. Accordingly, by definition, the main difference between traditional AD and ACLF is the short- and medium-term prognosis.Key pointPatients with ACLF have significantly poorer outcomes than those with traditional decompensation.Table 1The EASL-CLIF definition of Acute-on-Chronic Liver Failure (ACLF).7Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437.e1–e9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042Abstract Full Text Full Text PDF PubMed Scopus (1769) Google Scholar, 23Jalan R. Saliba F. Pavesi M. Amoros A. Moreau R. Ginès P. et al.Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.J Hepatol. 2014; 61: 1038-1047https://doi.org/10.1016/j.jhep.2014.06.012Abstract Full Text Full Text PDF PubMed Scopus (568) Google ScholarThe CLIF Consortium-organ failure scoring system (CLIF-C OF score)Organ/systemSubscore = 1Subscore = 2Subscore = 3Liver (total bilirubin, mg/dl)<6≥6–<12≥12Kidney (creatinine, mg/dl)<2≥2–<3.5≥3.5 or RRTBrain (West-Haven grade HE)01–23–4Coagulation (INR)<2≥2–<2.5≥2.5Circulation (MAP, mmHg)≥70 300 or≤300–>200 or≤200 or SpO2/FiO2>357≤357–>214≤214The shaded area describes criteria used to define organ failures. ACLF grade 1 (ACLF-1): patients with single kidney failure, patients with non-renal organ failure plus renal dysfunction (creatinine 1.5–1.9 mg/dl) and/or brain dysfunction (grade 1–2 HE). ACLF-2: patients with two organ failures. ACLF-3: patients with three or more organ failures. CLIF, chronic liver failure; RRT, renal replacement therapy; HE, hepatic encephalopathy; INR, international normalized ratio; MAP, mean arterial pressure; FiO2, fraction of inspired oxygen; PaO2, partial pressure of arterial oxygen; SpO2, pulse oximetric saturation. Open table in a new tab Patients with ACLF have significantly poorer outcomes than those with traditional decompensation. The shaded area describes criteria used to define organ failures. ACLF grade 1 (ACLF-1): patients with single kidney failure, patients with non-renal organ failure plus renal dysfunction (creatinine 1.5–1.9 mg/dl) and/or brain dysfunction (grade 1–2 HE). ACLF-2: patients with two organ failures. ACLF-3: patients with three or more organ failures. CLIF, chronic liver failure; RRT, renal replacement therapy; HE, hepatic encephalopathy; INR, international normalized ratio; MAP, mean arterial pressure; FiO2, fraction of inspired oxygen; PaO2, partial pressure of arterial oxygen; SpO2, pulse oximetric saturation. In the CANONIC study, Kaplan-Meier plots of the probability of survival revealed significantly poorer outcomes among patients with ACLF compared to those with traditional AD (Fig. 1).[7]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437.e1–e9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042Abstract Full Text Full Text PDF PubMed Scopus (1769) Google Scholar Of note, the two curves separated very early, indicating that great effort should be made to improve patient care during the first days of the syndrome, or before it occurs. Moreover, responses to classical management of cirrhosis complications can be modulated by the presence and/or the grade of ACLF. One study observed that the response rate of hepatorenal syndrome to terlipressin plus albumin was 60% for patients with ACLF grade 1 (ACLF-1) compared to 29% for patients with ACLF-3.[10]Piano S. Schmidt H.H. Ariza X. Amoros A. Romano A. Hüsing-Kabar A. et al.Association Between Grade of Acute on Chronic Liver Failure and Response to Terlipressin and Albumin in Patients With Hepatorenal Syndrome.Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2018; https://doi.org/10.1016/j.cgh.2018.01.035Abstract Full Text Full Text PDF Scopus (84) Google Scholar Another showed that, in the case of severe alcoholic hepatitis (sAH), the response rate to corticosteroids was 77% in patients without ACLF compared to 38% in those with ACLF.[11]Sersté T. Cornillie A. Njimi H. Pavesi M. Arroyo V. Putignano A. et al.The prognostic value of acute-on-chronic liver failure during the course of severe alcoholic hepatitis.J Hepatol. 2018; 69: 318-324https://doi.org/10.1016/j.jhep.2018.02.022Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar These data highlight the need to tailor therapeutic strategies and time frames to the presence of ACLF. They also suggest that emerging alternative therapies should be assessed in ACLF. The nature of the precipitating events leading to ACLF differs according to country and can be categorised into hepatic or extrahepatic insults. One of the core differences in ACLF definitions is the origin of the precipitating event. Indeed, while EASL-CLIF and NACSELD-defined ACLF includes both hepatic or extrahepatic insults (such as bacterial infection and variceal bleeding), APASL-defined ACLF only includes hepatic insults. In Western countries, the most commonly identified precipitating factors are bacterial infection, recent excessive alcohol use in the past three months (potentially sAH), and gastrointestinal haemorrhage (Table 2).[7]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437.e1–e9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042Abstract Full Text Full Text PDF PubMed Scopus (1769) Google Scholar In Asia, classically, the most frequent precipitating hepatic insult is HBV reactivation and, less frequently, superimposed HEV and HAV.12Shi Y. Yang Y. Hu Y. Wu W. Yang Q. Zheng M. et al.Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults.Hepatol Baltim Md. 2015; 62: 232-242https://doi.org/10.1002/hep.27795Crossref PubMed Scopus (209) Google Scholar, 13Garg H. Kumar A. Garg V. Sharma P. Sharma B.C. Sarin S.K. Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure.Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2012; 44: 166-171https://doi.org/10.1016/j.dld.2011.08.029Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar Recently, a large multicentre study from the APASL ACLF research consortium (AARC) reported that alcohol consumption within the last four weeks represented nearly half of precipitating hepatic events, while HBV reactivation explained only 15% of cases.[14]Choudhury A. Jindal A. Maiwall R. Sharma M.K. Sharma B.C. Pamecha V. et al.Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models.Hepatol Int. 2017; 11: 461-471https://doi.org/10.1007/s12072-017-9816-zCrossref PubMed Scopus (101) Google Scholar Controversies remain regarding the maximum duration of alcohol abstinence (four weeks or three months) permitted for alcohol consumption to be considered a trigger of ACLF. Of note, the European experience has shown that 13.5% of patients with established ACLF had two precipitating factors or more (Table 2).[7]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437.e1–e9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042Abstract Full Text Full Text PDF PubMed Scopus (1769) Google Scholar Interestingly, in ∼44% of patients in the CANONIC study, the development of ACLF was not preceded by an identifiable precipitating factor.[7]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437.e1–e9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042Abstract Full Text Full Text PDF PubMed Scopus (1769) Google ScholarTable 2Precipitating events in patients with traditional AD, ACLF, and in the whole cohort (CANONIC study).*Adapted from 7. Values are n (%).EventTraditional AD(n = 1,040)ACLF(n = 343)All patients(N = 1,343)Bacterial infection226 (21.8)98 (32.6)324 (24.1)Active alcoholism within the past 3 months147 (14.9)69 (24.5)216 (16.1)Gastrointestinal haemorrhage180 (17.3)40 (13.2)220 (16.4) Other event34 (3.5)25 (8.6)59 (4.4) More than 1 event56 (5.7)39(13.5)95 (7.1) No event584 (58.9)126 (43.6)710 (52.9)* Adapted from [7]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437.e1–e9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042Abstract Full Text Full Text PDF PubMed Scopus (1769) Google Scholar. Values are n (%). Open table in a new tab The pathophysiology of ACLF is still unclear. However, there is some information available on the landscape of systemic inflammation in AD. Compared to healthy individuals, patients with traditional AD exhibit features of systemic circulatory dysfunction (SCD) (i.e., high plasma levels of renin and copeptin), and systemic inflammation (i.e., high plasma levels of cytokines and chemokines).[15]Clària J. Stauber R.E. Coenraad M.J. Moreau R. Jalan R. Pavesi M. et al.Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.Hepatology. 2016; 64: 1249-1264https://doi.org/10.1002/hep.28740Crossref PubMed Scopus (419) Google Scholar Compared to patients with traditional AD, those with ACLF have much more marked SCD and systemic inflammation.[15]Clària J. Stauber R.E. Coenraad M.J. Moreau R. Jalan R. Pavesi M. et al.Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.Hepatology. 2016; 64: 1249-1264https://doi.org/10.1002/hep.28740Crossref PubMed Scopus (419) Google Scholar Of note, patients with AD have full-blown inflammation, involving pro- and anti-inflammatory cytokines. Since systemic inflammation can cause SCD, it has been suggested that inflammation-induced SCD, via tissue hypoperfusion, drives the development of end-organ failure in cirrhosis.[16]Bernardi M. Moreau R. Angeli P. Schnabl B. Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis.J Hepatol. 2015; 63: 1272-1284https://doi.org/10.1016/j.jhep.2015.07.004Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar Experimental results suggest that inflammation could drive organ dysfunction/failure through induction of SCD and subsequent tissue hypoperfusion. For example, in arteriolar walls, cytokine-induced nitric oxide production can result in vasorelaxation, a major component of SCD. However, it has recently been shown that the strength of the association of ACLF with excessive systemic inflammation is significantly higher than with SCD.[15]Clària J. Stauber R.E. Coenraad M.J. Moreau R. Jalan R. Pavesi M. et al.Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.Hepatology. 2016; 64: 1249-1264https://doi.org/10.1002/hep.28740Crossref PubMed Scopus (419) Google Scholar These findings suggest that the amplification of systemic inflammation could trigger organ failures, at least in part, independently of SCD worsening, raising the question of whether immune cells modulated by cytokines and chemokines play a major role in the development of organ failures. Indeed, outside the context of cirrhosis, there is evidence that intense systemic inflammation may lead to organ dysfunction/failure through direct deleterious effects on microcirculatory homeostasis, mitochondrial function, and cell survival.[17]Gomez H. Ince C. De Backer D. Pickkers P. Payen D. Hotchkiss J. et al.A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury.Shock Augusta Ga. 2014; 41: 3-11https://doi.org/10.1097/SHK.0000000000000052Crossref PubMed Scopus (488) Google Scholar This hypothesis is reinforced by evidence in the kidney. Indeed, it has been shown in renal biopsies of patients with cirrhosis that cortical and medullary infiltration by mononuclear cells and polymorphonuclear leukocytes with tubular cell injury was independently associated with the presence of renal failure.[18]Trawalé J.-M. Paradis V. Rautou P.-E. Francoz C. Escolano S. Sallée M. et al.The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study.Liver Int Off J Int Assoc Study Liver. 2010; 30: 725-732https://doi.org/10.1111/j.1478-3231.2009.02182.xCrossref PubMed Scopus (133) Google ScholarKey pointWhile the pathogenesis of ACLF remains unclear, a hallmark of the condition is excessive systemic inflammation, which could trigger organ failures. While the pathogenesis of ACLF remains unclear, a hallmark of the condition is excessive systemic inflammation, which could trigger organ failures. Environmental (e.g., bacterial infection, 'binge' alcohol drinking) and non-environmental (e.g., gastrointestinal haemorrhage) precipitating factors are expected triggers of systemic inflammation in ACLF. It is important to note that similar precipitating factors have been found for traditional AD (Table 2). Thus, which mechanisms explain why, for a given precipitating factor, some patients will develop ACLF while others will develop traditional AD has become one of the major questions in the field. We should be aware that mechanistic differences could be dependent on the origin (intrahepatic vs. extrahepatic insults), the type (alcohol-induced liver injury, viral hepatitis, bacterial infection) of the trigger event, and the history of chronic liver disease (presence or absence of previous decompensation). For example, in the context of bacterial infection, differences in severity may be related to differences in environmental factors (characteristics of infecting bacteria), host non-genetic factors (age), and host genetic factors that increase predisposition to the development of severe sepsis.[19]Moreau R. The pathogenesis of ACLF: the inflammatory response and immune function.Semin Liver Dis. 2016; 36: 133-140https://doi.org/10.1055/s-0036-1583199Crossref PubMed Scopus (62) Google Scholar Future research is needed to elucidate mechanisms of excessive inflammation in response to identified precipitating events. Precipitating events are not detected in a substantial proportion of patients with traditional AD (with low grade inflammation) and ACLF (with high grade inflammation) (Table 2). One cannot exclude the existence of a bacterial infection that routine diagnostic methods failed to detect. Alternatively, patients with cirrhosis but without overt infection may have increased intestinal permeability allowing bacterial by-products (e.g., lipopolysaccharide) to translocate into the systemic circulation.[20]Arroyo V. Moreau R. Kamath P.S. Jalan R. Ginès P. Nevens F. et al.Acute-on-chronic liver failure in cirrhosis.Nat Rev Dis Primer. 2016; 2: 16041https://doi.org/10.1038/nrdp.2016.41Crossref PubMed Scopus (85) Google Scholar In this scenario, bacterial products would induce inflammation through their recognition by the innate immune system. If this hypothesis is true, it would raise important questions relating to how differences in the intensity of systemic inflammation between patients with traditional AD and those with ACLF can be explained. The outcomes in cirrhotic patients with AD and ACLF and those with traditional AD differ dramatically in short- and intermediate-term analyses. In the CANONIC study, the 28-day and 3-month mortality rates were respectively, 33% and 51% in patients with ACLF, and 5% and 13% in patients with traditional AD (Fig. 1).[7]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437.e1–e9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042Abstract Full Text Full Text PDF PubMed Scopus (1769) Google Scholar This last figure shows that some patients with traditional AD have a substantial risk of short-term mortality. A prognostic score (CLIF-Consortium AD [CLIF-C AD] score) was developed especially for this group of patients based on the variables associated with medium-term mortality (age, serum sodium, log-transformed white cell count, serum creatinine, and INR).[21]Jalan R. Pavesi M. Saliba F. Amorós A. Fernandez J. Holland-Fischer P. et al.The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure.J Hepatol. 2015; 62: 831-840https://doi.org/10.1016/j.jhep.2014.11.012Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar A CLIF-C AD score equal to or lower than 45 predicted a very low 90-day mortality rate (2%) and a score of 60 or higher was associated with 90-day mortality rate of 31%. This score was externally validated and seems to be useful for discriminating patients with AD who can be discharged early from those who require specific attention to prevent complications and development of ACLF. When a patient fulfils ACLF diagnostic criteria, we have several potential tools for estimating outcomes. Based on the CANONIC study, the baseline grade of ACLF, the clinical course of the syndrome, and a specific score (CLIF-Consortium ACLF [CLIF-C ACLF] score) can accurately predict outcomes. The initial grade of ACLF is defined according to the number of OFs and the presence of kidney and/or neurological dysfunction (Table 1). The 28-day and 90-day mortality rates are 22% and 41% for ACLF-1, 32% and 52% for ACLF-2, and 77% and 79% for ACLF-3, respectively.[7]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144 (1437.e1–e9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042Abstract Full Text Full Text PDF PubMed Scopus (1769) Google Scholar Moreover, in the CANONIC experience, ACLF was found to be a dynamic syndrome characterised by probabilities of resolution or improvement of 49%, stabilisation of 30%, and worsening of 20%.[22]Gustot T. Fernandez J. Garcia E. Morando F. Caraceni P. Alessandria C. et al.Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.Hepatology. 2015; 62: 243-252https://doi.org/10.1002/hep.27849Crossref PubMed Scopus (375) Google Scholar The clinical course of ACLF is a more accurate predictor of short-term outcomes than its initial grade. In the CANONIC study, the majority of patients with ACLF (81%) reached their final ACLF grade between the 3rd and 7th day after diagnosis (day 3–7 ACLF) making this time point an ideal moment to assess prognosis.[22]Gustot T. Fernandez J. Garcia E. Morando F. Caraceni P. Alessandria C. et al.Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.Hepatology. 2015; 62: 243-252https://doi.org/10.1002/hep.27849Crossref PubMed Scopus (375) Google Scholar Investigators also developed a prognostic score for patients with ACLF. A simplified form of the CLIF-SOFA score has been developed: the CLIF-C OF score, which is formulated by sub-scoring each organ system using a 3-point range (Table 1). Finally, a third score, called CLIF-C ACLF score, that incorporates the CLIF-C OF score, age and white blood cell count has been designed on the CANONIC data and validated in an independent cohort of critically ill cirrhotic patients.[23]Jalan R. Saliba F. Pavesi M. Amoros A. Moreau R. Ginès P. et al.Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.J Hepatol. 2014; 61: 1038-1047https://doi.org/10.1016/j.jhep.2014.06.012Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar This CLIF-C ACLF score consistently improved prediction error rates by ∼20% for 28-day and 90-day mortality compared to classical scores (model for end stage liver disease [MELD], MELD-Na, and Child-Pugh). In a recent large study of cirrhotic patients admitted to the intensive care unit (ICU), the c-statistics of the CLIF-C ACLF score were 0.7 and 0.68 for 28-day and 90-day mortality and not better than those for the MELD score, questioning its accuracy and utility in decision-making for therapeutic management.[24]Karvellas C.J. Garcia-Lopez E. Fernandez J.
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